The present invention relates to novel methods of using known pharmacological agents in man. The invention further relates to novel compositions employing these known pharmacological agents for the treatment of various conditions or diseases in animals. Particularly, the present invention relates to the use of these known pharmacological agents in the treatment of pathological cardiovascular ischemic states (PACVIS) in animals and man.
The cardiovascular ischemic states whose treatment comprises the subject matter of the present invention are those states arising from physiological processes, particularly frankly pathological processes in which necrosis develops in smooth or striated muscles or skin.
The cardiovascular ischemic state, which leads to the development of necrosis in the cardiac muscle, includes, for example, angina, vasospastic angina, the sudden death syndrome, and the like. The ischemia resulting from these states is well known and is readily diagnosed by an attending physical or veterinarian.
The cardiovascular ischemic states directly involving necrosis of smooth or striated muscle or skin include a wide variety of diseases and conditions. Further, certain cardiovascular ischemic states are a recognized untoward consequence of numerous other diseases and conditions.
One principle class of cardiovascular ischemic states is a consequence of the various forms or types of vasospasms. Vasospasms refers to the abnormal spasm of the blood vessels, resulting in decrease in their caliber. Ischemic in this invention refers to the condition of having local and temporary deficiency of blood, due to the contraction of a blood vessel.
Although it is known that the pharmacological agents now found to be useful in the treatment of pathological cardiovascular ischemic states were previously known for use as anti-allergenic agents, the mechanism for such previously known use is not appreciated. It is known that histamine plays a role in allergic reactions. Further this amine is a potent, easily released and functional endogenous compound in the body. For example, mast cells are the cells having granules in which histamine is highly concentrated. Histamine acts on two separate and distinct receptors, termed H.sub.1 and H.sub.2 receptors. Both H.sub.1 and H.sub.2 receptors mediate the vasodilator effects of histamine. Thus, the mast cells function in the healthy vertebrate by the release of histamine. However, the specific influences of the mast cell on ischemia is not well understood. For this reason, advantages of the present invention patentably extend methods of treating pathological cardiovascular ischemic states (PACVIS). See Goth et al., "Histamine", Medical Pharmacology, chap. 15, pp. 177-188, 9th ed., C. V. Mosby Co., St. Louis, (1978).
Vasospasm is a condition common in adults and typically results in a deficiency of blood to muscle or skin which is then at risk of developing necrosis. Vasospasms typically result in numerous systematic manifestations, characterized by ischemic disorders. Various types of vasospasms associated with ischemia are known. See for example, The Merck Manual, 13th edition, Merck, Sharp and Dohme Research Laboratories, Rahway, N.J. (1977). Among the types of vasospasms are those which produce angina pectoris attributed to myocardial ischemia. These vasospasms may progress to myocardial infarction, attributable to ischemic myocardial necrosis following an abrupt reduction in coronary flow to a segment of the myocardium. Vascular spasm may also contribute to occlusion of the abdominal aorta and its branches, such as splanchnic artery occlusion, renal artery occlusion, or occlusion at the bifurcation, and peripheral vascular disorders consequent to occlusive arterial diseases. Other notable disease states whose principle long term pathology arises from vasospasms as a constituent thereof include functional peripheral arterial disorders, such as Reynaud's phenomenon, acrocyanosis, and, rarely, erythromalagia. For example, Reynaud's disease may be idiopathic or secondary to such conditions as occlusive arterial disease. Likewise, such pathology may result from connective tissue disorders; such as, progressive systemic sclerosis, neurogenic lesions, drug intoxication, dysproteinemias, myxedema, primary pulmonary hypertension, and trauma. Much less severe in its ultimate effect is the cardiovascular ischemic state resulting from acrocyanosis.
Other disease conditions also induce pathological cardiovascular ischemic states (PACVIS) with resulting untoward effects on the affected animal. For example, arterial embolism or thrombosis may be due to a number of causes in an animal having a history of ischemia associated with vasospasms. Further, in many peripheral vascular diseases the vasospastic disorders induce pathological cardiovascular ischemic states with resulting pathological consequences.
Other vasospastic diseases also have the effect of inducing a pathological cardiovascular ischemic state, for example, immersion foot, trench foot, herpes zoster, decubitous ulcers, and diabetic gangrene.
Finally, while many cardiovascular ischemic states have been attributed in the past to excess vasospasm, measuring the extent of ischemia is a more recent development. Consequently, limiting the extent of the ischemia has likewise been difficult. For example, it has long been known in myocardial infarction that cardiac peformance after recovery depends essentially on the mass of functioning muscle surviving the acute episode. Reinfarction or extension of infarct during hospitalization is common. The use of increased inspired O.sub.2 concentration is one avenue of treatment. Recent animal studies suggest that reduction of the O.sub.2 requirements of myocardium and an increase in coronary perfusion or reduction of after load with vasodilators reduce the area of ischemic infarction. The primary effects may be based on the lowering of peripheral resistance. These observations need further evaluation but in selected patients, especially those with elevated pressures, it appears to be appropriate in the acute stages of infarction to use vasodilators. These include such known agents as nitroglycerin, isosorbide dinitrate, trimethafan, or nitroprusside.
Measuring the ischemic myocardium at risk of necrosis is discussed by DeBoer et al. in "Autoradiographic Method for Measuring the Ischemic Myocardium at Risk: Effects of Verapamil on Infarct size after Experimental Coronary Artery Occlusion", Proc. Natl. Acad. Sci. U.S.A., vol. 77, no. 10, pp. 6119-6123, October, 1980, Medical Sciences. Such measurement in the investigation of pharmacological agents is advantageous since myocardial infarct size appears to be a function of ischemia myocardium at risk of developing necrosis. Numerous methods have been reported for assessing the effectiveness of pharmacological agents including by indirect methods. For example, one such report indicates determination of epicardial enosis. See Kloner, R. A. et al., Circulation, vol. 58, pp. 220-226 (1978). Another indirect method is described as "Factors Influencing Infarct Size Following Experimental Coronary Artery Occlusions" by Maroko, P. R. et al., Circulation, vol. 43, pp. 67-82 (January, 1971). Direct methods include postmortem injection of dyes described by Reimer, K. A. et al. Lab. Invest., vol. 40, pp. 633-644 (1979) or angiographic contrast agents described by Jugdutt, B. I. et al., Circulation, vol. 60, pp. 1141-1150 (1979), Jugdutt, B. I. et al., Circulation, vol. 59, pp. 734-743 (1979), Hoffman, M. et al. Circulation, vol. 60, II-215A (ABSTR.) (1979).
An efficient means of assessing the inhibition of cardiovascular ischemic states by a chemical agent is described by DeBoer et al., cited above. The method of DeBoer et al. determines the ability of a chemical agent to affect infarct size. The first objective of this study is to determine the physiological status of coronary blood flood after the coronary arterial occlusion but prior to the administration of drugs. The second objective of this study is to use autoradioagraphy to test the efficacy of delayed administration of the drug, in this case verapamil, in reducing myocardiam infarction size.
The technique of DeBoer et al. for measuring the reduction of myocardial infarct size employs the techniques described in the above noted DeBoer et al. article. Thirty minutes after left anterior decending coronary occlusion mongrel dogs are randomized into control or treatment groups. Ischemic bed size (area at risk) is determined both before treatment by the injection of 99m Tc labeled albumin microspheres with postmortem autoradioagraphy (AR-R) and during treatment by left atrial dye injection immediately before sacrifice (AR-D). Infarct size (IS) is determined six hours after coronary arterial occlusion by triphenyl tetrazolium staining and expressed as percent of left ventrical before occlusion.
In summary, the compounds of this invention are substituted in the DeBoer et al. techniques. By measuring their inhibition of the ischemic state, it is understood that the spread of necrosis is likewise inhibited which consequently reduces the size of the infarction following a coronary occlusion.
It is by this method that the efficacy of the known compounds are evaluated for the instant invention.
The known compounds employed in the novel methods and compositions disclosed herein are previously known as anti-allergenic agents specifically including disodiumchromoglycate (DSCG) and DSCG anti-allergenic biologues. Hereinafter DSCG and DSCG anti-allergenic biologues are referred to in the invention by the term "biologues." These biologues include anti-allergenic bis chromones related to DSCG. Both DSCG and bis chromones related to DSCG are described in U.S. Pat. No. 3,419,578. Further related anti-allergenic bis chromones are those described in U.S. Pat. Nos. 3,519,652 and 3,673,218. Moreover, additional compounds of the invention biologues, including anti-allergenic uses therefore, are described in U.S. Pat. No. 4,046,910, issued Sept. 6, 1977. The description of DSCG and related anti-allergenic bis chromones which are the biologues of the present invention and their anti-allergenic compositions are incorporated here by reference from U.S. Pat. Nos. 3,419,578, 3,519,652, 3,673,218, and 4,046,910.
Another class of compounds within the biologues of the present invention are the anti-allergenic benzopyrans, particularly the compounds described in U.S. Pat. Nos. 4,159,273, 3,786,071, 3,952,104, and 4,055,654. Notable among these compounds is proxicromil (FPL 57,787), 6,7,8,9-tetrahydro-5'-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2--ca rboxylic acid, described in Example 8 of U.S. Pat. No. 4,159,273. The description and anti-allergenic compositions of these anti-allergenic benzopyrans are incorporated here by reference from U.S. Pat. Nos. 4,159,273, 3,786,071, 4,055,654, and 3,952,104.
Yet, another class of compounds within the biologues of the present invention are the anti-allergenic oxamic acids or derivatives thereof. These compounds, together with their anti-allergenic uses and compositions, are described in U.S. Pat. Nos. 3,993,679, 4,159,278, 4,095,028, 4,089,973, 4,011,337, 4,091,011, 3,972,911, 4,067,995, 3,980,660, 4,044,148, 3,982,006, 4,061,791, 4,017,538, 4,119,783, 4,113,880, 4,128,660, 4,150,140, 3,966,965, 3,963,660, 4,038,398, 3,987,192, 3,852,324, and 3,836,541. The preparations of such compounds and their anti-allergenic compositions are incorporated by reference here from the aforementioned United States patents. The most preferred biologue in the present invention is the dioxamate N,N'-(2-chloro-5-cyano-m-phenylene)dioxamic acid (lodoxamide). Among lodoxamides preferred forms are the bis THAM, (tris(hydroxymethyl)-amino methane) salt and the diethyl ester, particularly the diethyl ester.